Intrauterine deposit

ABSTRACT

An intrauterine system for the retention of a biologically active compound within the uterus of a female mammal is formed by a frame defining an interior space for receipt of a deposit of the compound. The frame has an open structure allowing access to a substantial part of an outer surface of the deposit and the deposit has a rate controlling structure that controls a rate of release of the compound within the uterus. Retention elements are provided on the frame for retaining the frame within the uterus.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates generally to intrauterine systems and inparticular to devices that are capable of retaining and releasing abiologically active compound within the uterus. The invention furtherrelates to a method of manufacturing an intrauterine system having abiologically active compound deposited therein.

2. Description of the Related Art

The use of intrauterine devices (IUDs) has long been recognised as aconvenient manner of providing long-term contraception. The presence ofa device within the uterus causes the release of leukocytes andprostaglandins by the endometrium or uterine lining. These substancesare hostile to both sperm and eggs and are understood to preventfertilisation and any subsequent attachment of the fertilised egg to theendometrium. The use of copper in an IUD increases the spermicidaleffect.

An IUD that has been widely accepted is presently marketed by N.V.Organon under the name Multiload™. Such a device is depicted in U.S.Pat. No. 3,952,734 and comprises an elongated stem carrying at one endtwo resilient, cantilevered arms, extending sideways on either side ofthe stem. A copper wire is wound about the stem. For insertion into theuterine cavity the stem is contained within a tube shaped sheath bymeans of which the device may be inserted through the cervix. The sheathnarrowly encloses the stem and the shape and flexibility of the arms arechosen such that they can collapse around the sheath during insertion.The sheath may then be pulled back and the arms unfold to retain the IUDwithin the uterus. For the purpose of retrieval, a thread is attached tothe stem at the opposite end from the arms. The thread extends throughthe cervix and can be pulled for removal of the device. Under normalcircumstances the IUD may be effectively used for long periods of up to5 years without removal.

More recently, devices have been developed that can include a quantityof a hormone for long term retention and release within the uterus.These devices are generally referred to as intrauterine systems (IUS)and the term will be used hereafter to refer to IUDs having anincorporated agent. One system is marketed by Schering AG under the nameMirena™. The system comprises a T-shaped polyethylene frame with asteroid reservoir around the stem. The reservoir consists of a cylindermade of a mixture of levonogestrel and silicone. The reservoir iscovered by a silicone membrane which controls the release rate to about20 micrograms per day for a period of 3 to 5 years. Insertion andremoval of the system is generally similar to that described above. Sucha system is shown in U.S. Pat. No. 4,341,728. The use of steroids mayenhance the contraceptive effect and also contribute tonon-contraceptive health benefits of the system. Copper coil type IUDstend to increase bleeding during a woman's menstrual cycle. Using ahormone based IUS, menstrual bleeding may be reduced or even stop. Localadministration of hormones also allows lower dosages to be used comparedto other hormonal methods for contraception whose primary mode of actionis suppression of ovarian function. Another device that uses a dose of aprogestogen to augment the effect of a copper coil is shown in Germanpatent DE 4125575 C. According to the document, the progestogen may beprovided in crystalline form in the head of the IUD and its release ratecontrolled by diffusion through fine pores or a perforation.Alternatively, it may be mixed in a silicone-gelatine material or arubber based material and applied externally to the IUD.

To effectively control the pharmacodynamic properties, a system must beable to store a sufficient dose of agent to ensure a sufficient fluxover a prolonged period, yet small enough to prevent injury or pain onpassing through the cervix. Another difficulty encountered inmanufacturing an IUS is the need to produce a structure that is strongenough to endure the forces of insertion, removal and usage withoutbreaking yet again is small enough to prevent injury or pain on passingthrough the cervix. In particular, the connection between the arms andthe stem must be flexible to allow folding of the arms around or withinthe inserter. On removal the arms must again fold without breaking off,since loss of part of the device within the uterus could lead tocomplications. One device that attempts to solve these problems is shownin U.S. Pat. No. 7,080,647, in which arms are attached to a slot in amedicated fibre stem. The strength of the device appears to be dependentupon the limited material available for the slot connection. Anotherdevice is known from WO96/01092 in which a medicated deposit is used toform the arms of the device and the stem comprises a loop that encirclesthe arms.

A further difficulty lies in ensuring correct dosage of the agent. Priordevices use rate controlling membranes surrounding the agent. The needfor integrity of the membrane has required complicated mouldingprocedures for connecting the body of the device to the agent deposit.EP1400258 and WO06/079709 describe solutions for manufacture of IUSs. Anumber of other IUSs are disclosed in which a quantity of agent isprovided e.g. as a coating at an external surface of the device

Another alternative device is known from U.S. Pat. No. 3,656,483 whichdiscloses a tubular body having perforations that allow for the releaseof a biologically active material. The material is in the form of aseries of pellets that are biased towards the perforations by a springmember. Leaching of the medication takes place at the perforated regionand the rate of release is controlled by the passage of the agentthrough the perforations. As each pellet is dissolved, the remainingpellets are pushed downwards by the spring. In this manner a series ofdifferent agents may be released successively. Nevertheless, the releaserate of each agent is dependent upon the interrelation between theformulation and the perforations in the tubular body. Any blockages ofthe perforations would affect the subsequent release of the medication.The strength of the structure is provided by the external tube, whichmay make device insertion more difficult and painful.

It would be desirable to be able to manufacture a simple device in whichthe release rate of the medication or agent could be easily predicted.The rate should also be reliably maintained in practice. Furthermore,the construction of the device should be simple and involve a minimumnumber of components and yet be both strong and flexible and smallenough to allow easy insertion.

BRIEF SUMMARY OF THE INVENTION

The present invention addresses these problems by providing anintrauterine system for the retention of a biologically active compoundwithin the uterus of a female mammal, preferably a human. The systemcomprises a deposit of the compound, the deposit comprising a ratecontrolling structure that controls a rate of release of the compoundwithin the uterus, a frame defining an interior space for receipt of thedeposit, the frame having an open structure allowing access to asubstantial part of an outer surface of the deposit and having one ormore retention elements for retaining the frame within the uterus.Because of the open structure of the frame the greater part of thesurface of the inserted deposit is directly exposed to the environmentand hence the rate controlling effect on the steady state release of thecompound to the uterus may be primarily determined by the structure ofthe deposit itself and the environment in which it is placed. This isextremely beneficial from a manufacturing perspective since once theframe is defined, existing drug formulations or controlled releasecapsules/fibers may be inserted into the frame. As release rates areprimarily determined by the deposits themselves, release rates withinthe frame should be relatively easily predictable.

The invention may thus also be considered to provide an intrauterinesystem comprising a frame for receipt of a deposit of a biologicallyactive compound, wherein the frame is an open structure facilitatingrelease of the compound to the uterus. In the following, reference to anopen structure allowing access to a substantial part of an outer surfaceof the deposit is understood to cover an arrangement in which at least50% of the outer surface of the deposit is exposed. Preferably, morethan 60% of the outer surface will be exposed and more preferably morethan 70% will be exposed.

The invention further relates to an intrauterine system for theretention of a biologically active compound within the uterus of afemale mammal, comprising a deposit of the compound in the form of agenerally rod shaped element, a substantially flexible frame defining aninterior space for receipt of the deposit and retention elementsprovided on the frame for retaining the frame within the uterus, whereinthe flexible frame and the rod shaped element interact to form acomposite structure having greater mechanical strength, in particularstiffness, than either the frame or the rod shaped element alone.Accordingly, an improved structure may be achieved that ensures adequatestrength while still ensuring ease of insertion due to the smallcross-section of the frame that may be achieved in this manner.

Preferably, the frame stem may have a diameter of less than 4.5 mm, yetmore preferably less than 4.0 mm, and may even be less than 3.5 mm indiameter. As the skilled person will understand, for use in combinationwith a tubular inserter, for surrounding the stem, it is of significancethat the IUS is able to fit within an inserter having an outer diameterof 5.0 mm. In this manner compliance may be achieved with ISO-7439.2002,which for human recipients requires an insertion tube of not more than5.0 mm outer diameter.

According to a preferred embodiment of the invention, the framecomprises an opening for allowing introduction of the deposit into theinterior space and a closure member for closing the opening. The openingis preferably located at a forward end of the frame. Once inserted intothe interior space, the deposit is thus safely retained againstaccidental removal from the frame. Alternatively, either the frame orthe deposit or both may be sufficiently flexible to allow insertion ofthe deposit into the frame and its subsequent retention.

Preferably, the closure member comprises a plug. The plug may beintegrally formed with the frame or may be a separate component.Although use of a plug or cap is preferred, the skilled man willunderstand that alternative closures may be used. In particular, theframe may be formed of two parts that join together around the depositto contain it. Both parts may be connected to close the opening usingmechanical means such as press fitting, form fitting, screw thread orthe like. Alternatively, the parts may be glued, welded or otherwisebonded together. In a preferred embodiment, the plug is substantiallyimpermeable and can cover and protect an end of the deposit as will bedescribed below.

Most preferably, the frame is formed of a substantially inert material.In this context the term “substantially inert material” is intended torefer to a material that is not eroded by exposure to the environmentwithin the uterus and does not itself actively release an agent.Nevertheless, by the nature of intrauterine devices, it is not excludedthat the frame can cause release of leukocytes and prostaglandins by theendometrium. In a most preferred embodiment the frame comprises abiologically compatible polymer, in particular polyethylene (PE),ethylene vinyl acetate (EVA) or a combination thereof. Such polymershave been found to exhibit sufficient strength and resilience for suchapplications. According to a further preferred embodiment, either theframe or the deposit or both may incorporate an indicator such as aradio-opaque material. Barium sulphate is a preferred substance for thispurpose.

In a preferred embodiment of the invention, the one or more retentionelements are integrally formed with the frame. The retention elementsmay take any form that ensures the function of retaining the devicewithin the uterus, including but not limited to an arm or arms, coilstructures, anchors, hooks, barbs, fibres and the like. Of importancehowever is that the retention elements also allow insertion and removalof the device into and from the uterus as appropriate. The frame maypreferably comprise an elongate stem in which is located the interiorspace and the retention elements may then be formed as arms, laterallyextending from the stem. The interior space may also be formed at leastpartially within the retention elements or arms as appropriate. Variousforms of arm are well known in the art.

The invention is intended for use with any appropriate deposit. Anadvantage of the present design is that one form of frame may bemanufactured and used as a basis for different deposits carryingdifferent compounds according to the desired treatment. A preferred formof deposit comprises a polymer matrix in which the active agent orcompound is dissolved or otherwise dispersed. Preferably the matrix isloaded with a progestogen selected from the group consisting ofnomegestrol acetate (NOMAc), natural progesterone, levonogestrel,etonogestrel, dydrogesterone, medrogestone, medroxyprogesterone acetate,megestrol acetate, chlormadinone acetate, cyproterone acetate,gestonorone caproate, demegestone, promegestone, nesterone,trimegestone, norethisterone (norethindrone), norethisterone acetate,lynestrenol, ethinodiol acetate, norethinodrel, norgestrel,norgestimate, dienogest, gestodene, drospirenone, and any other suitablesteroidal compound with progestogenic activity. Most preferably thematrix is loaded with etonogestrel within the range of 10-70% wtetonogestrel, but more preferably 30-65 wt % and yet most preferably40-65 wt %. The core matrix may comprise an EVA polymer, preferably anEVA material with >10% vinyl acetate (VA), more preferably >15 % VA%.

According to a further preferred embodiment the rate controllingstructure comprises a membrane surrounding the matrix. The membranepreferably also comprises EVA, in particular EVA with a VA percentage oflower than 40%, preferably lower than 33% and most preferably lower than28%. Such a construction is believed to be most advantageous in ensuringa controlled release of the compound at a steady rate over a prolongedperiod. Since the membrane forms part of the deposit rather than theframe, each may be optimised independently of the other.

According to a further aspect of the invention, the deposit issubstantially form stable and is not eroded during use. Due to the factthat the deposit is not eroded, there is little danger that it couldexit from the open structure of the frame during prolonged retention inthe uterus. In particular, the frame may be provided with largeopenings. Another attribute of a form stable deposit is that themechanical integrity of the IUS remains intact due to interaction of theframe and deposit.

According to a still further aspect of the invention, the deposit may bemanufactured in the form of a rod shaped element having acircumferential surface and two end surfaces. Preferred dimensions forthe rod are 1.5-3.0 mm diameter and 20-45 mm in length for a single rodalthough under some circumstances diameters as low as 1.0 mm may providesufficient release. In general, the dimensions may be largely dictatedby standards bodies such as according to the above-mentionedISO-7439.2002, which limits the overall length of an IUD to 36 mm. Itwill also be understood that different dimensions may be applicable e.g.if the deposit were to be located within an arm of an IUD device. Suchdeposits have been found convenient to manufacture by extrusionprocesses and may be subsequently cut into desired lengths for use. Inparticular, a deposit may be formed by a co-extrusion process to form arod shaped polymer matrix surrounded by a release rate determiningmembrane. On cutting the extruded rod into lengths, the exposed ends arenot covered by the membrane. In this case, it is desirable that theframe covers the two end surfaces to prevent or reduce release ofcompound from these regions in particular, the initial burst oncommencing use. In this case in particular, it is the membrane aroundthe circumferential outer surface of the deposit that is exposed by theopen structure of the frame. To maximise the dosage retained in thedeposit and/or to increase the strength of the system, the rod mayextend substantially the whole length of the IUD.

The present invention also relates to a method of forming anintrauterine system, the method comprising forming a frame having aninterior space and an open structure, providing a deposit of abiologically active compound, the deposit having an outer surfaceprovided with a rate controlling structure and inserting the depositinto the interior space such that a substantial part of the outersurface is exposed through the open structure. In particular, theprovision of a deposit of a biologically active compound may involveproviding the compound in an existing galenical form for insertion intothe frame.

Preferably, the method further comprises applying a closure to anopening in the frame to prevent removal of the deposit from the interiorspace. The application of the closure may comprise bonding the closureto the frame to prevent removal thereof and may take place in anautomated procedure e.g. by gluing, welding or hot stamping. Asindicated above, in a preferred embodiment, the opening and its closureis located at a forward end of the frame.

In a further preferred embodiment the method comprises forming thedeposit by co-extrusion of a polymer matrix containing the compound anda rate controlling membrane.

According to yet another aspect of the invention the method may compriseforming the frame by injection moulding. The frame and its closure maybe formed in a single moulding operation or alternatively may be formedas two distinct components e.g. using different materials.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of the invention will be further appreciatedupon reference to the following drawings, in which:

FIG. 1 is a perspective view of a first embodiment of the invention;

FIG. 2 is a sectional view of the IUD of FIG. 1 along line 2-2;

FIG. 3 is a perspective view of a second embodiment of the invention;

FIG. 4 is a perspective view of a third embodiment of the inventionprior to assembly;

FIG. 5 is a perspective view of the embodiment of FIG. 4 after insertionof a deposit;

FIG. 6 is a perspective view of a fourth embodiment of the invention;

FIG. 7 is a perspective view of a fifth embodiment of the inventionduring insertion of a deposit,

FIG. 8 is a perspective view of a sixth embodiment of the invention; and

FIG. 9 is a perspective view of an inserter and IUD assembly accordingto the present invention.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Referring to FIG. 1, there is shown an intrauterine system 1 accordingto a first embodiment of the invention. The IUD 1 has a body 2comprising a stem 4 with a pair of laterally extending arms 6 connectedat its upper end 8. At a lower end 10 of the stem 4, there is providedan eye 12 to which is connected a nylon thread 14. The stem 4 is formedby a frame 16 having openings 18 to an interior space 20. Within theinterior space 20 is located a rod shaped deposit 22.

FIG. 2 shows a cross-sectional view through the IUD 1 taken along line2-2. FIG. 2 shows more clearly the frame 16 of the stem 4 and thedeposit 22 received within the interior space 20. FIG. 2 also shows thedeposit 22 to comprise a core 24 and an outer membrane 26. Core 24 isformed of a matrix consisting of EVA copolymer with a vinyl acetatepercentage of 28%, to which a quantity of biologically active compoundhas been added. In the present embodiment, the core 24 is loaded withetonogestrel at 54 wt % with respect to other core materials. Theskilled person will be aware that other medications or biologicallyactive compounds may be incorporated and that other loadings may beconsidered. Additionally, the core 24 comprises 12 wt % of BaSO₄ as aradio opaque indicator. The membrane 26 has a thickness of around 40microns and consists of EVA copolymer with a vinyl acetate percentage of15%. The skilled person will be aware that other membrane dimensions andcompositions may be used, as determined by the desired release rate ofthe active compound from the core 24. The deposit 22 has an overalllength of 30 mm and a diameter of around 2.3 mm. The stem 4 has anoverall length of about 36 mm and external diameter of about 3.2 mm.

Manufacture of the IUD 1 takes place by injection moulding of the body 2in a single piece including stem 4 and arms 6. To this end, the body 2comprises a PE/EVA mixture including barium sulphate in a 44/36/20 wt %mixture. The presence of barium sulphate improves x-ray visibility ofthe finished product. The thread 14 is then attached to eye 12 by asimple hitch. After forming the body 2, the rod shaped deposit 22 isinserted into the frame 16 by passing it through one of the openings 18and sliding it towards the upper end 8. The deposit 22 is sufficientlyflexible to allow it to bend slightly into an S-shape such that theother end of the deposit 22 can be inserted into the lower end 10 of thestem 4. The frame 16 is also flexible and assists insertion of thedeposit 22. The deposit 22 is now effectively retained within the frame16 and cannot exit without being manipulated by a user. The IUD is thenready for use and can be conventionally inserted into the uterus of auser by a medical practitioner using an otherwise conventional inserter.

FIG. 3 depicts a second embodiment of an IUD 100 according to theinvention in which like reference numerals preceded by a 1 will be usedto represent the same features as in the system of FIGS. 1 and 2.According to FIG. 3, IUD 100 comprises a body 102 having a stem 104. Thestem 104 is formed by a helical coil 116 having openings 118 and aninterior space 120. The coil 116 is preferably made of metal but couldalso be a moulded plastic component. Arms 106 are integrally formed withan upper end 108 of the stem 104 in which the coil 116 is embedded by amoulding procedure. A lower end 110 of the stem 104 is also formed as amoulding and provided with an eye 112 to which is connected thread 114.A deposit 122 is retained in the interior space 120. The deposit 122 maybe generally identical to that of FIGS. 1 and 2. Insertion of thedeposit 122 into interior space 120 takes place by deformation of thecoil 116. Although the thread 114 is depicted as attaching to the lowerend 110, it may also be desirable to pass it through the stem 104 toattach at the upper end 108. In this manner, tension on the thread 114to extract the IUD 100 will not cause stretching of the coil 116.

FIGS. 4 and 5 depict a third embodiment of an IUD 200 according to theinvention in which like reference numerals preceded by a 2 will be usedto represent the same features as in the system of FIGS. 1 and 2.According to FIG. 4, the IUD 200 comprises a body 202 having a stem 204formed in two frame halves 205, 205′ having snap elements 209. Eyes 212,212′ are formed at lower ends 210, 210′ of frame halves 205, 205′. Anupper end 208 of the stem 204 carries a pair of arms 206.

The body 202 is formed in an injection moulding procedure having livinghinges 207, 207′ between the frame halves 205, 205′ and the upper end208. After insertion of a deposit 222, the frame halves 205, 205′ aresnapped together to form the stem 204 as shown in FIG. 5. The deposit222 is now retained in interior space 220. Deposit 222 may be generallyidentical to that of FIGS. 1 and 2. Thread 214 is then passed througheyes 212, 212′ further restraining the frame halves 205, 205′ fromopening.

A fourth embodiment of an IUD 300 according to the invention isdisclosed according to FIG. 6 in which like reference numerals precededby a 3 are used to represent the same features as in the system of FIGS.1 and 2.

IUD 300 is generally similar to the embodiment of FIG. 1 and comprises abody 302 comprising a stem 304 with a pair of laterally extending arms306 connected at its upper end 308. At a lower end 310 of the stem 304,there is provided an eye 312 to which is connected a nylon thread 314.The stem 304 is formed as a frame 316 having openings 318 to an interiorspace 320. Within the interior space 320 is located a rod shaped deposit322. Unlike the embodiment of FIG. 1, IUD 300 also includes a cap 330covering an opening 332 formed through the upper end 308. The cap 330has a smooth outer surface that blends into the upper end 308. The cap330 allows insertion of the deposit 322 during manufacture of the IUD300. After insertion the opening 332 is closed by the cap 330 which isfixed in place by a welding procedure. Alternatively or additionally,the cap 330 may be glued to the body 302 using an appropriate adhesiveor may be hot stamped thereto, or any other appropriate technique.

FIG. 7 depicts a fifth embodiment of an IUD 400 according to theinvention in which like reference numerals preceded by a 4 are used torepresent the same features as in the system of FIGS. 1 and 2.

Referring to FIG. 7, the IUD 400 has a body 402 comprising a stem 404with a pair of laterally extending arms 406 connected at its upper end408. As in previous embodiments, stem 404 is formed as a generally openframe 416. A lower part of the stem 404 is however formed as twoflexible legs 405, 405′ having mating lower ends 410, 410′. Eyes 412,412′ are formed in the lower ends 405, 405′.

The body 402 is formed in an injection moulding procedure and the legs405, 405′ are sufficiently flexible that they can be spread apart forinsertion of a deposit 422. After insertion, the legs 405, 405′ returnto their original positions. A thread 414 is then passed through eyes412, 412′ to restrain the legs 405, 405′ from opening so that thedeposit 422 is retained in interior space 420. Legs 405, 405′ may alsobe provided with snap connectors (not shown) at their lower ends 410,410′.

FIG. 8 depicts a sixth embodiment of an IUD 500 according to theinvention in which like reference numerals preceded by a 5 are used torepresent the same features as in the system of FIGS. 1 and 2.

Referring to FIG. 8, the IUD 500 comprises a pair of flexible arms 506,506 joined together connected at their lower ends 510. Each arm 506′,506 carries at its upper end 508 an open frame 516, integrally formedtherewith. An eye 512 is formed at lower end 505 to receive a thread514. As can be seen, one arm 506 is longer than the other 506′ and bothare sufficiently flexible that they can be folded together for insertionof the IUD into an insertion tube, whereby the frames 516 substantiallyalign with one another within the tube. Each frame 516 comprises aninterior space 520 in which a deposit 522 is retained as in previousembodiments.

FIG. 9 shows an inserter 600 for introduction of any of the IUDs 1, 100,200, 300, 400 and 500. The inserter 600 comprises a thin-walled hollowtube 602 having an outer diameter of 3.9 mm and an inner diameter ofapproximately 3.3 mm. A slideable ruler element 604 is mounted on thetube 602 to assist a medical practitioner in correct positioning of thedevice. IUD 1 is initially in a retracted position within the inserterwith only the arms 6 exposed at a first end 606 of the inserter 600. Thethread 14 extends from a second end 608 of the inserter 600, where itcan be held by the practitioner. Insertion of the IUD takes place in anotherwise conventional manner and will not be further described here indetail. The IUDs of the present invention may also be used with otherinserter arrangements in which the IUD is provided at the end of a wandor holder, rather than within a tubular element. Furthermore, althoughthe arms 6 of the IUD are shown folded around an outside of the insertertube in the embodiment of FIG. 9, it will be understood that they mayalso be folded together within the inserter instead.

The invention has thus been described by reference to certainembodiments discussed above. It will be recognized that theseembodiments are susceptible to various modifications and alternativeforms well known to those of skill in the art without departing from thespirit and scope of the invention. In particular, although allembodiments have been shown with laterally extending, curved arms, othershapes are possible including but not limited to straight, branched andcurled arms. Other forms of retention elements may alternatively oradditionally be used to maintain the system within the uterus.Accordingly, although specific embodiments have been described, theseare examples only and are not limiting upon the scope of the invention.

1-24. (canceled)
 25. An intrauterine system for retention of abiologically active compound within the uterus of a female mammal, thesystem comprising: a deposit comprising a core and an outer membrane,wherein the core comprises etonogestrel and, wherein the outer membranecontrols a rate of release of the etonogestrel within the uterus andwherein the core and the outer membrane are substantially form-stableand not eroded during use; a frame defining an interior space forreceipt of the deposit, the frame having an open structure that extendslongitudinally along the frame and allows access to a substantial partof the outer membrane of the deposit; and one or more retention elementsfor retaining the frame within the uterus.
 26. The system according toclaim 25, wherein the frame is flexible and interacts with the depositto form a mechanical structure having a stiffness greater than that ofeither the deposit or the frame alone.
 27. The system according to claim25, wherein the deposit is in the form of a rod shaped element having acircumferential surface and two end surfaces.
 28. The system accordingto claim 25, wherein the frame comprises an opening for allowingintroduction of the deposit into an interior space and a closure memberfor closing the opening.
 29. The system according to claim 28, whereinthe closure member comprises a substantially impermeable plug.
 30. Thesystem according to claim 28, wherein the closure member is located at aforward end of the frame and a retrieval element is located at arearward end of the frame.
 31. The system according to claim 25, whereinthe frame is formed of a substantially inert material.
 32. The systemaccording to claim 31, wherein the substantially inert material is abiologically compatible polymer.
 33. The system according to claim 25,wherein the retention elements are integrally formed with the frame. 34.The system according to claim 25, wherein the deposit comprises apolymer matrix core.
 35. The system according to claim 34, wherein thepolymer matrix core comprises an ethylene vinylacetate polymercomprising more than 10% vinyl acetate and the deposit has a diameter offrom 1.0 mm to 3.0 mm.
 36. The system according to claim 25, wherein thedeposit comprises a rate controlling structure comprising the outermembrane surrounding the deposit, wherein the outer membrane comprisesan ethylene vinylacetate polymer having less than 40% vinyl acetate. 37.The system according to claim 25, wherein the frame having an openstructure allows access to at least 50% of a surface of the deposit. 38.The system according to claim 25, wherein the deposit comprises two endsurfaces and the frame covers the two end surfaces to prevent release ofcompound therefrom.
 39. The system according to claim 25, wherein theframe comprises an elongate stem in which is located an interior spaceand the retention elements comprise arms, laterally extending from thestem.
 40. The system according to claim 25, further comprising aninserter comprising a hollow tube into which the frame may be received.41. The system according to claim 40, wherein the inserter has an outerdiameter of less than 4.0 mm.
 42. The system according to claim 25,wherein the female mammal is a human female.
 43. An intrauterine systemfor retention of a biologically active compound within the uterus of afemale mammal, the system comprising: a generally rod shaped depositcomprising a core and an outer membrane, wherein the core comprisesetonogestrel, and wherein the core and the outer membrane aresubstantially form-stable and not eroded during use; a substantiallyflexible frame defining an interior space and having an open structurethat extends longitudinally along the frame for receipt of the deposit,wherein the flexible frame and the rod shaped deposit interact to form acomposite structure having greater stiffness than either the rod shapeddeposit or the frame alone; and one or more retention elements providedon the frame for retaining the frame within the uterus.
 44. The systemaccording to claim 43, wherein the female mammal is a human female. 45.A method of forming an intrauterine system comprising: forming a framehaving an interior space and an open structure that extendslongitudinally along the frame; providing a deposit comprising a coreand a rate controlling outer membrane, wherein in the core comprisesetonogestrel, and wherein the core and the rate controlling outermembrane are substantially form-stable and not eroded during use; andinserting the deposit into the interior space such that a substantialpart of the rate controlling outer membrane is exposed through the openstructure.
 46. The method according to claim 45, further comprisingclosing an opening in the frame to prevent removal of the deposit fromthe interior space.
 47. The method according to claim 45, furthercomprising bonding a closure to the frame to prevent removal of thedeposit.
 48. The method according to claim 45, wherein the frame isformed by injection moulding.
 49. The method according to claim 45,further comprising forming the deposit by co-extrusion of a polymermatrix core containing the compound and a rate controlling membrane. 50.The method according to claim 45, wherein the female mammal is a humanfemale.
 51. A method of contraception in a female mammal, the methodcomprising placing the intrauterine system according to claim 25 intothe uterus of the mammal.
 52. The method according to claim 51, whereinthe female mammal is a human female.
 53. A method of contraception in afemale mammal, the method comprising placing the intrauterine systemaccording to claim 43 into the uterus of the mammal.